The assessment of genetically determined predispositions to clinical diseases is a theme central to the vision of a personalized health care. Rare deleterious germline mutations have been found to cause up to 150 different primary immunodeficiencies. In most instances, there is predisposition to multiple infectious diseases. However, it is now becoming apparent that rare mutations in some genes can result in more subtle/narrow clinical phenotypes. This study aims at establishing an ex-vivo genome-wide transcriptome assay to measure leukocyte responses to host- and pathogen-derived immune activators in such patients. Specifically, we are first proposing to characterize blood leukocyte responsiveness in control subjects. This aim will use whole genome expression microarrays to assess responsiveness in whole blood of 12 healthy subjects exposed to Toll-like and Interleukin 1 receptor family ligands. Secondly, we will identify specific alterations in patterns of blood leukocyte responsiveness in the blood of patients with known inborn errors of TLR immunity. This aim will assess responsiveness of 18 subjects with increased susceptibility to invasive pneumococcal disease attributed to a defect in function of two key signaling molecules: IRAK4 and MYD88. Altogether this project will serve as a foundation for the development of novel tools to screen for and characterize primary immune deficiencies.